morphine-3-glucuronide and Body-Weight

Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy.. Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models.. The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants.. M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.

Topics: Aging; Analgesics, Opioid; Body Weight; Child, Preschool; Drug Administration Schedule; Female; Half-Life; Humans; Infant; Infant, Newborn; Male; Models, Biological; Morphine; Morphine Derivatives; Pain, Postoperative; Single-Blind Method

To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure.. Prospective pharmacokinetic-pharmacogenomic observational study.. Thirteen PICUs across the United States.. Pediatric subjects (n = 66) mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.. Serial blood sampling for drug quantification and a single blood collection for genomic evaluation.. Concentrations of morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed-effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified.. The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.

Topics: Acute Disease; Adolescent; Age Factors; Analgesics, Opioid; Body Weight; Child; Child, Preschool; Critical Illness; Female; Genotype; Glucuronosyltransferase; Humans; Infant; Male; Morphine; Morphine Derivatives; Pharmacogenomic Testing; Prospective Studies; Respiration, Artificial; Respiratory Insufficiency; Time Factors

Concentrations of morphine and its 3- and 6-glucuronide metabolites (M3G and M6G) in plasma, brain, and urine of rats exposed to morphine for either 24 or 48 h were measured using high-performance liquid chromatography. In another group of morphine-treated rats, the intensity of naloxone-precipitated withdrawal behaviours was monitored at 24 and 48 h. The behavioural effects of M3G in opiate-naive and opiate-dependent rats were also investigated. Morphine was present in plasma, urine, and brain at 24 and 48 h, whereas M3G was detected in plasma and urine only. M6G was not present in detectable quantities in either plasma, urine, or brain. Although plasma concentrations of M3G were similar in both time groups, rats treated for 48 h had significantly larger quantities of M3G in their urine than did the other treatment groups. The incidence of withdrawal behaviour was significantly higher in animals exposed to morphine for 48 h than in those with only 24 h of exposure, M3G had no behavioural effects in the opiate-naive rats and did not precipitate an opiate-abstinence syndrome in morphine-dependent rats. From these results, it was concluded that although M3G is the major product formed by morphine breakdown in rats, it is unlikely that it is involved in the development of morphine dependence in this species.

Topics: Animals; Body Weight; Brain; Defecation; Female; Morphine; Morphine Dependence; Morphine Derivatives; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Substance Withdrawal Syndrome

In patients with renal failure, morphine may cause prolonged narcosis and respiratory depression. Accumulation of the pharmacologically active metabolite morphine-6-glucuronide (M-6G) may explain this effect of morphine in patients with renal failure. After a single oral dose, morphine and its conjugates were measured in the plasma and the cerebrospinal fluid (CSF) in patients with renal failure.. Eight patients with normal renal function and six patients with renal failure requiring dialysis were studied after operation under spinal anesthesia. Plasma and CSF concentrations of morphine, morphine-3-glucuronide (M-3G), and M-6G were measured by high-pressure liquid chromatography every 4 h for 24 h after an oral dose of 30 mg morphine.. The area under morphine plasma concentration-time curve from 0 to 24 h increased from 38 +/- 4 ng.ml-1 x h in patients with normal renal function to 110 ng.ml-1 x h in those with renal failure (P < 0.01). In patients with renal failure, plasma concentrations of M-3G and M-6G were higher at 4 h and remained at an increased level until the end of the study. The peak CSF concentration of morphine at 8 h was similar in those with renal failure or normal renal function, 1.8 +/- 0.4 and 2.0 +/- 0.6 ng.ml-1 respectively. M-3G and M-6G in CSF reached a maximum at 12 h in patients with normal renal function, whereas in those with renal failure the concentrations gradually increased so that the highest concentrations were observed at 24 h. At 24 h, CSF M-6G concentration was 15 times greater in patients with renal failure than in those with normal renal function.. We conclude that M-3G and M-6G readily cross the blood-brain barrier in patients with normal renal function or with renal failure. In patients with renal failure, the retention of plasma M-6G induces a progressive accumulation of this active metabolite in CSF; this accumulation may explain the increased susceptibility to morphine in patients with renal failure.

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood-Brain Barrier; Body Weight; Humans; Kidney; Middle Aged; Morphine; Morphine Derivatives; Renal Insufficiency